The development of COX2 inhibitors with improved biochemical selectivity (such as etoricoxib and valdecoxib) over that of commercially available coxibs has been driven by the potential advantage of safety using higher coxib doses for increased efficacy. Etoricoxib has been approved in the UK as a once-daily medicine for symptomatic relief in the treatment of osteoarthritis (OA), rheumatoid arthritis (RA) and acute gouty arthritis. It is currently approved with additional indications (i.e., for relief of acute pain associated with dental surgery, for primary dysmenorrhoea and for chronic musculo-skeletal pain, including chronic lower-back pain) in Mexico, Brazil and Peru. Etoricoxib has an in vitro COX1/COX2 IC(50) ratio of 344, the highest of any coxib. The administration of therapeutic doses of etoricoxib to healthy subjects does not affect COX1 activity in circulating platelets and gastric biopsies. The profound inhibition of monocyte COX2 activity at 24 h after dosing, as predicted by a pharmacological half-life of approximately 22 h, supports a once-daily dosing regimen of etoricoxib. In randomised, well-controlled clinical trials, etoricoxib has been shown to have a comparable clinical efficacy with traditional NSAIDs. Combined analysis of efficacy trials with etoricoxib versus non-selective NSAIDs has shown that the drug halves both investigator-reported upper gastrointestinal perforation, ulcers and bleeds (PUBs) and confirmed PUBs, and reduces the need for gastroprotective agents and gastrointestinal comedications by approximately 40%. The risk of lower extremity oedema and hypertension adverse experiences with etoricoxib was low and generally similar to comparator NSAIDs in a combined analysis of eight Phase III studies in OA, RA, chronic low-back pain and surveillance endoscopy. Large, randomised clinical trials have been planned to confirm the renal, gastrointestinal and cardiovascular safety of etoricoxib.

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The development of nonsteroidal anti-inflammatory drugs (NSAIDs) selective for cyclooxygenase (COX)-2 (named coxibs) has been driven by the aim of reducing the incidence of serious gastrointestinal (GI) adverse events associated with the administration of traditional (t) NSAIDs – mainly dependent on the inhibition of COX-1 in GI tract and platelets. However, their use has unravelled the important protective role of COX-2 for the cardiovascular (CV) system, mainly through the generation of prostacyclin. In a recent nested-case control study, we found that patients taking NSAIDs (both coxibs and tNSAIDs) had a 35% increase risk of myocardial infarction. The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin by coxibs and tNSAIDs can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity. However, most tNSAIDs and coxibs are functional COX-2 selective for the platelet (ie, they cause a profound suppression of COX-2 associated with insufficient inhibition of platelet COX-1 to translate into inhibition of platelet function), which explains their shared CV toxicity. The development of genetic and biochemical markers will help to identify the responders to NSAIDs or who are uniquely susceptible at developing thrombotic or GI events by COX inhibition. We will describe possible strategies to reduce the side effects of etoricoxib by using biochemical markers of COX inhibition, such as whole blood COX-2 and the assessment of prostacyclin biosynthesis in vivo.

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Background: Platelet–cancer cell interactions modulate tumor metastasis and thrombosis in cancer. Platelet-derived extracellular vesicles (EVs) can contribute to these outcomes. Methods: We characterized the medium-sized EVs (mEVs) released by thrombin-stimulated platelets of colorectal cancer (CRC) patients and healthy subjects (HS) on the capacity to induce epithelial-mesenchymal transition (EMT)-related genes and cyclooxygenase (COX)-2(PTGS2), and thromboxane (TX)B2 production in cocultures with four colorectal cancer cell lines. Platelet-derived mEVs were assessed for their size distribution and proteomics signature. Results: The mEV population released from thrombin-activated platelets of CRC patients had a different size distribution vs. HS. Platelet-derived mEVs from CRC patients, but not from HS, upregulated EMT marker genes, such as TWIST1 and VIM, and downregulated CDH1. PTGS2 was also upregulated. In cocultures of platelet-derived mEVs with cancer cells, TXB2 generation was enhanced. The proteomics profile of mEVs released from activated platelets of CRC patients revealed that 119 proteins were downregulated and 89 upregulated vs. HS. Conclusions: We show that mEVs released from thrombin-activated platelets of CRC patients have distinct features (size distribution and proteomics cargo) vs. HS and promote prometastatic and prothrombotic phenotypes in cancer cells. The analysis of platelet-derived mEVs from CRC patients could provide valuable information for developing an appropriate treatment plan.